1. Field of the Invention
The present invention relates to compounds that show an anti-inflammatory action and are useful as pharmaceuticals
2. Summary of the Related Art
At present, the majority of medicines widely used as anti-inflammatory agents are non-steroid anti-inflammatory drugs (NSAIDs) that have, as the mechanism of action, an inhibitory action on cyclooxygenases (COXs) that is involved in the biosynthesis of prostanoids. However, since prostanoid synthesis activity is present in various tissues in the living body and governs the homeostasis thereof, various side effects are induced when NSAID is administered. For example, PGE2 demonstrates the action of maintaining blood flow in the stomach and kidneys, whereas administration of NSAIDs makes it difficult to maintain local blood flow, thereby causing gastric or renal disorders.
Under such circumstances, the presence of a COX isozyme has been confirmed. In order to distinguish it from the previously identified COX, the conventional type has been named COX-1, while the more recently discovered isozyme has been named COX-2. In addition, this COX-2 has been shown to be induced during inflammation and hardly be expressed under normal circumstances. It has also been shown that conventional NSAID are able to non-specifically inhibit both COX-1 and COX-2 enzymes. Therefore, a compound having COX-2 inhibitory action would be useful as an anti-inflammatory agent.
There are currently several compounds that are known to preferentially inhibit COX-2 whilst having significantly less COX-1 inhibitory activity. However, the actions of these compounds are not satisfactory and since some of them do not have an adequate water solubility or oral absorption, there remains a need for a drug that demonstrates more effective COX-2 inhibitory action.
Vioxx or 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone (rofecoxib) belongs to the group of NSAIDs known as COX-2 selective inhibitors or coxibs (CycloOXygenase-2 InhiBitors). Being COX-2 selective means that these drugs act preferentially on one form of the cyclooxygenase (COX) enzyme, namely the COX-2, whereas earlier NSAIDs inhibited both COX-1 and COX-2 with little if any selectivity. This specificity allows rofecoxib and other COX-2 inhibitors to reduce inflammation and pain while minimizing undesired gastrointestinal adverse effects, e.g. peptic ulcers are common with non-selective NSAIDs such as aspirin, naproxen, and ibuprofen.
Moreover it has been shown that there is an increased risk of cardiovascular events associated with the use of rofecoxib, valdecoxib and parecoxib and these compounds were withdrawn from the market.
Nevertheless, nonsteroidal anti-inflammatory drugs (NSAIDs) have been successfully administered to treat pain and inflammation for many years. The analgesic, antipyretic and anti-inflammatory properties of aspirin and other NSAIDs were explained by the inhibition of prostanoid synthesis by suppressing cyclooxygenase (COX) activity. This finding not only explains the mechanism of action of NSAIDs, but also reveals a useful pharmacological tool for evaluating the physiological role of prostanoids by COX inhibition. NSAIDS are the most frequently used drugs worldwide, based on the fact that they are administered to treat large numbers of patients for many systemic pathological conditions, including chronic polyarthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, gout, inflammatory soft tissue rheumatism, lower back pain, post-operative and post-traumatic inflammation, thrombophlebitis, vasculitis, and certainly rheumatoid arthritis Dermatologic conditions including erythema nodosum, nodular acne, prurigo nodularis, palmoplantar pustulosis, and psoriasis that could lead to psoriatic arthritis, have also been treated by NSAIDs. However, as noted above, long-term use of NSAIDs is associated with gastrointestinal (GI) erosion and renal failure.
Prostanoids (PGs) are widely distributed throughout the gastrointestinal tract. Inhibition of PG synthesis is the principal underlying mechanism for GI mucosal erosion. Endogenous prostaglandin E2 (PGE2), derived from both COX-1 and COX-2, has been shown to be involved in mucosal defense by decreasing gastric acid secretion, which is mediated by prostaglandin E2 receptor (EP) type 3 (EP3) in rats. PGE2 has a dual action on gastric acid secretion in rats, with the inhibitory effect mediated by EP3 receptors and the stimulatory effect through EP4 receptors. In mice, EP3 but not EP1 receptors are essential for acid-induced duodenal HCO3− secretion and mucosal integrity. Endogenous PGI2, also has a protective role in gastric mucosal integrity in mice. Unlike in rodents, EP1 receptors are not found in any type of cells in the human gastric mucosa.
In the kidney, prostanoids uphold the balance between vasodilatation and vasoconstriction. They also regulate renin secretion, tubular transport processes, and cell fate. PGI2 signaling is essential for maintenance of renal homeostasis and renal function, which is supported by the fact that COX-2 and PGI synthase (PGIS) knockout mouse models display significant disturbances in the kidney. The preferential association between COX-2 and PGIS in PGI2 biosynthesis was evidenced by the fact that the renal phenotype of PGIS knockout mice closely resembles the one shown in COX-2 knockout animals, while no major abnormalities in COX-1 knockout mice were apparent. The same association is also presented in humans. On the other hand, PGE2 regulates renal hemodynamics and salt and water excretion via prostanoid receptors EP1-4, where EP1 and EP3 act as constrictors, and EP2 and EP4 as dilators. The bidirectional capacity of PGE2 to modulate vascular tone and epithelial transport allows PGE2 to serve as a buffer to prevent physiological disturbances. Therefore, both PGE2 and PGI2 are crucial prostanoids in regulating normal kidney function. Their inhibition by NSAIDs results in sodium retention and hypertension, which could cause acute renal failure.
Cyclooxygenases (COXs), COX-1 and COX-2, also known as prostanoid H synthases (PGH synthase), are the key enzymes in the synthesis of prostanoids from arachidonic acid released from membrane phospholipids. The major difference between these two enzymes remains that COX-1 is constitutively expressed as a “housekeeping enzyme” involved in physiological functions in many cells, whereas COX-2 is usually expressed inducibly and transiently. Because of the expression patterns of the two isoforms of COX, it was assumed that COX-1-derived prostanoids were involved in regulating physiological functions, whereas COX-2-derived prostanoids played a major role in inflammation or tissue damage. According to this hypothesis, the pharmacological effects of NSAIDs depend on the inhibition of COX-2, whereas the toxic organ-specific effects in GI tissue and kidney are linked to the inhibition of COX-1. Therefore, as noted above, COX-2 selective inhibitors (COXIBs) were developed as anti-inflammatory agents to minimize the side effects associated with NSAIDs. However, in reality, COX-2 also plays a physiological role in certain tissues and organs, and COX-1 may be involved in inflammatory reactions. “Constitutive” expression has also been observed for both isoforms of COX in the kidney, spinal cord, and brain.
While there is no obvious advantage of COXIBs over nonselective NSAIDS in terms of renal toxicity, significantly fewer GI complications have been reported in patients treated with COXIBs. However, selective inhibition of COX-2 causes an imbalance between COX-2 derived PGI2 and COX-1 derived TXA2, which results in serious cardiovascular risk. TXA2 is a major prostanoid released from activated platelets by COX-1 to stimulate platelet aggregation and vasoconstriction. To counter the biological effects of TXA2, PGI2, a dominant product of COX-2 under physiological conditions in vascular endothelial cells, acts as a protective constraint on thrombogenesis, hypertension, and atherogenesis. The imbalance in favor of TXA2 resulting from the clinical use of COXIBs disrupts vascular homeostasis and, thus increases vulnerability to thrombosis, atherosclerosis, and hypertension; particularly in patients genetically susceptible to cardiovascular disease. The withdrawal of the selective COX-2 inhibitors rofecoxib and valdecoxib have emphasized the cardioprotective role of prostacyclin.
Although clearly demonstrated by the long and wide use of the NSAIDs/COXIBs that prostanoids are critical inflammatory mediators, each prostanoid, PGD2, PGF2α, PGI2, TXA2, and particularly PGE2, might sometimes be anti-inflammatory. Most importantly, the cardiovascular, renal, and gastrointestinal toxicities associated with the NSAIDs/COXIBs must be addressed. It seems like that EP3 receptors should be spared from blockade because of their roles in GI protection, and IP receptors should be preserved because of their importance in cardiovascular and renal homeostasis, while it might be necessary to block TP receptors because of their cardiovascular liability in clinical use of COXIBs.
Prostamide antagonist are known from published U.S. Patent Application Nos. 2008/0696240, 2005/0054699 and 2006/0106078. PGD2 antagonists are known from published US Patent Application No. 2004/0162333.
An object of the present invention is to provide compounds that have FP, DP, EP1, EP4 and TP inhibitory activity, but lack EP2, EP3 and IP activity and are useful as pharmaceuticals.